The present invention is directed to a method of synthesizing libraries of diverse and complex 2-substituted azole derivatives and novel intermediate compounds. The invention is further directed to methods for synthesizing the libraries on solid supports.
Compounds having biological activity can be identified by screening diverse collections of compounds (i.e., libraries of compounds) produced through synthetic chemical techniques.
The generation of chemical libraries on and off solid resins have proven to be a valuable resource for the pharmaceutical industry in their endeavors to discover new drugs using high throughput screening (HTS) techniques. In creating the libraries, the compounds are ideally synthesized in situ in solution phase or on a solid support. However, relatively simple synthetic methods to produce a diverse collection of such derivatives in situ are often not available.
Such screening methods include methods wherein each member of the library is tagged with a unique identifier tag to facilitate identification of compounds having biological activity or where the library comprises a plurality of compounds synthesized at specific locations on the surface of a solid substrate wherein a receptor is appropriately labeled to identify binding to the compound, e.g., fluorescent or radioactive labels. Correlation of the labeled receptor bound to the substrate with its location on the substrate identifies the binding compound. Using these techniques, the development of efficient high throughput screening has greatly enhanced the pharmaceutical industry""s ability to screen large numbers of compounds for biological activity.
Central to these methods is the screening of a multiplicity of compounds in the library and the ability to identify the structures of the compounds that have a requisite biological activity. Preferably, in order to facilitate synthesis and identification, the compounds in the library are typically formed on solid supports wherein the compound is covalently attached to the support via a cleavable or non-cleavable linking arm. In this regard, libraries of diverse compounds are prepared and then screened to identify xe2x80x9clead compoundsxe2x80x9d having good binding affinity to the receptor.
Pharmaceutical drug discovery relies heavily on studies of structure-activity relationships wherein the structure of xe2x80x9clead compoundsxe2x80x9d is typically altered to determine the effect of such alteration on activity. Alteration of the structure of the lead compounds permits evaluation of the effect of the structural alteration on activity.
Thus, libraries of compounds derived from a lead compound can be created by including derivatives of the lead compound and repeating the screening procedures. In this manner, compounds with the best biological profile, i.e., those that are most active and which have the most ideal pharmacologic and pharmacokinetic properties, can be identified from the initial lead compound.
Recently, 2-substituted oxazoles were found to be potent as MMP inhibitors (Sheppard, et al, in Bioorg Med Chem Lett 8(22), 3251 (1998)); 2-substituted imidazoles were found to produce local anesthetic effects (Colombo, et al., Rev Farmacol Clin Exp, 4(1), 41-47 (1987); and 2-substituted thiazoles were found to be selective inhibitors of 5-lipoxygenase (Bird, et al., 5th Int Conf Inflamm Res Assoc (September 23-27 Whit Haven) Abst 85, 1990).
Synthesis of substituted nitrogen containing heteroaryls using solution phase chemistry has been previously described. Khristich et al., in Khimia Geterotsiklicheskikh Soedineii, 8, 1136-36 (1983) describe the solution phase synthesis of xcex1-(1-methyl-2-benzimidazolyl)benzyl benzoates. Roe et al., in JCS p 2195 (1963) describe the thermal condensation of imidazoles with carbonyl compounds. Papadopolous, in J. Org. Chem., 42 (24) 3925-29, (1977) describes reaction of imidazoles with isocyanates, while Papadopolous et al., in J. Org. Chem., 44(1) 99-104 (1979) describe reactions of azoles with isocyanates. Cleavage of the silicon-carbon bond of 2-trimethylsilyl-1-methylimidazole and 2-trimethylsilyl-1-benzimidazole to yield 2-substituted imidazoles and 2-substituted benzimidazoles is described by Pinkerton, F. H. and Thames, S. F., in J. Heterocycl. Chem. 9(1), 67-72 (1972). Dondoni et al., in J. Org. Chem., 53, 1748-61 (1988) describe the synthesis of (trimethylsilyl)thiazoles which are reacted with carbonyl compounds to prepared highly substituted thiazoles.
These methods however, do not permit for rapid synthesis of large libraries with diverse substitution patterns. Thus there exists a need for a solid phase method for synthesis of highly substituted azole compounds.
Accordingly, in order to develop new pharmaceutical drugs to treat various disease conditions, it would be highly desirable to be able to generate such libraries of substituted azole derivatives and novel intermediate compounds optionally attached to a solid support. Thus, there is a need for a facile in situ method for the generation of a multiplicity of substituted azole derivatives and novel intermediate compounds.
The present invention is directed to a process for assembly of diverse, 2-substituted azole derivatives and novel intermediate compounds using available azoles as starting materials. The rapid synthesis of such highly complex drug-like molecules is unexpected and surprising.
Accordingly, the invention is directed to a method of synthesizing highly substituted azole derivatives having the formula (I) or (II): 
wherein
X is selected from the group consisting of NH, NRA and S; 
represents a 5 membered aromatic ring structure; optionally containing one to two additional heteroatoms selected from the group consisting of N, O and S;
provided that the additional heteroatoms are not at the attachment point of the R2 group (i.e. the R2 group is always attached to a ring carbon);
provided that the 5 membered ring remains aromatic in nature;
wherein the 5 membered ring is optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, alkyl, alkenyl, halogenated alkyl, cycloalkyl, alkoxy, aryl, aralkyl, heterocyclyl, amino, mono-or di-substituted amino, cyano, nitro, xe2x80x94COOR, xe2x80x94COR, xe2x80x94SO2R and xe2x80x94CONRBRC; wherein the amine substituents are independently selected from alkyl, cycloalkyl, aryl or aralkyl; wherein the cycloalkyl, aryl or heterocyclyl may be further optionally substituted with one or more substituent is independently selected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino, mono-or di-substituted amino, cyano or nitro; 
represents a 9 membered ring structure, wherein the five membered portion of the ring structurexe2x80x94
xe2x80x94 is aromatic and the six membered portion of the ring structure xe2x80x94
xe2x80x94 is saturated, partially unsaturated, or aromatic;
wherein the 5 membered portion of the ring structure is optionally substituted with one to two substituents independently selected from the group consisting of halogen, hydroxy, alkyl, alkenyl, halogenated alkyl, cycloalkyl, alkoxy, aryl, aralkyl, heterocyclyl, amino, mono-or di-substituted amino, cyano, nitro, xe2x80x94COOR, xe2x80x94COR, xe2x80x94SO2R and xe2x80x94CONRBRC; wherein the amine substituents are independently selected from alkyl, cycloalkyl, aryl or aralkyl; wherein the cycloalkyl, aryl or heterocyclyl may be further optionally substituted with one or more substituent is independently selected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino, mono-or di-substituted amino, cyano or nitro;
wherein the 6-membered portion of the ring structure may further optionally containing one to four additional heteroatoms selected from the group consisting of N, O and S;
wherein the 6-membered portion of the ring structure may further be optionally substituted with one to four substituents independently selected from the group consisting of halogen, hydroxy, alkyl, halogenated alkyl, cycloalkyl, alkoxy, aryl, aralkyl, heterocyclyl, amino, mono-or di-substituted amino, cyano, nitro, xe2x80x94COOR, xe2x80x94COR, xe2x80x94SO2R and xe2x80x94CONRBRC; wherein the amine substituents are independently selected from alkyl, cycloalkyl, aryl or aralkyl; wherein the cycloalkyl, aryl or heterocyclyl may be further optionally substituted with one or more substituent independently selected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino, mono-or di-substituted amino, cyano or nitro;
R2 is selected from the group consisting of 
Z is selected from the group consisting of hydrogen, xe2x80x94OH, xe2x80x94OR, xe2x80x94NRARB, N(RA)ORB, xe2x80x94SR, xe2x80x94CN, xe2x80x94N3, and 
wherein 
represents a three to eight membered heterocyclyl group bound at the N atom, wherein the heterocyclyl group is saturated, partially unsaturated or aromatic; when the heterocyclyl group is a saturated six to eight membered heterocyclyl, the heterocyclyl group may optionally contains a group selected from O, CHR, NR, S, SO, or SO2, provided that that the group is separated from the N atom by at least two carbon atoms; and wherein the heterocylcyl group is optionally substituted with one or more substituents independently selected from R;
R3 is selected from the group consisting of hydrogen, alkyl, aralkyl, cycloalkyl, fluorinated alkyl, xe2x80x94COR, xe2x80x94COOR and xe2x80x94CONRBRC; wherein the aralkyl may be optionally substituted with one or more substituents independently selected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino, mono- or di-substituted amino, cyano or nitro;
R4 is selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, fluorinated alkyl, alkenyl, alkynyl, xe2x80x94COOR, xe2x80x94COR, xe2x80x94CONCND, -alkyl-COOR, heterocycle and 
wherein the alkyl, alkenyl, alkynyl, aryl, aralkyl or heterocycle may be optionally substituted with one or more substituents independently selected from halogen, hydroxy, alkyl, halogenated alkyl, aryl, alkoxy, aryloxy, amino, mono-or di-substituted amino, cyano or nitro; wherein Y is selected from the group consisting of O, S and NRA;
where R is selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, fluorinated alkyl and heterocycle; wherein the alkyl, aryl, aralkyl or heterocycle may be optionally substituted with one or more substituents independently selected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino, mono-or di-substituted amino, cyano or nitro;
where RA is selected from the group consisting of hydrogen, xe2x80x94R, xe2x80x94COOR, xe2x80x94COR, xe2x80x94SO2R and xe2x80x94CONRBRC and 
where RB and RC are independently selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, cycloalkyl, fluorinated alkyl and heterocycle; wherein the aryl, aralkyl or heterocycle may be optionally substituted with one or more substituents independently selected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino, mono-or di-substituted amino, cyano or nitro; or are joined together to form a 4 to 8 membered heterocyclyl ring structure;
which method comprises:
a) preparing a compound of the formula (III) or (V) on a solid support resin, 
wherein R3 and R4 are as described above;
b) cleaving the compound from the solid support resin by nucleophilic substitution to yield the corresponding compound of formula (I) or (II);
c) optionally further substituting the compound of formula (I) or (II) via alkylation reactions in solution phase.
As used herein, the term xe2x80x9calkylxe2x80x9d whether used alone or as part of a substituent group, shall denote straight and branched chains. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl and the like. Unless otherwise noted, xe2x80x9clowerxe2x80x9d when used with alkyl means a carbon chain composition of 1 to 4 carbon atoms. Similarly, as used herein, the term xe2x80x9calkenylxe2x80x9d, whether used alone or as part of a substituent group, shall denote straight and branched chain alkene radicals, i.e. straight of branched chains containing at least one double bond. For example, alkenyl radicals include allyl, vinyl, and the like. Similarly, as used herein, the term xe2x80x9calkynylxe2x80x9d, whether used alone or as part of a substituent group, shall denote straight and branched chain alkyne radicals, i.e., straight or branched chains containing at least one triple bond. For example, alkynyl radicals include xe2x80x94CCH, xe2x80x94CH2CCH (propargyl), xe2x80x94CH2CCCH3, and the like.
As used herein, unless otherwise noted, xe2x80x9calkoxyxe2x80x9d shall denote an oxygen ether radical of the above described straight or branched chain alkyl groups. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy, n-hexyloxy and the like.
As used herein, xe2x80x9chalogenxe2x80x9d shall mean chlorine, bromine, fluorine and iodine.
As used herein, unless otherwise noted, xe2x80x9carylxe2x80x9d shall refer to carbocyclic aromatic groups such as phenyl, naphthyl, and the like. Similarly, the term xe2x80x9caryloxyxe2x80x9d shall denote the oxygen ether radical of the above described aryl group, i.e. xe2x80x94O-(aryl). Suitable examples include phenyloxy, naphthyloxy, and the like.
As used herein, unless otherwise noted, xe2x80x9caralkylxe2x80x9d shall mean any lower alkyl group substituted with an aryl group such as phenyl, naphthyl and the like. Suitable examples of aralkyls include benzyl, 1-(phenyl)ethyl, naphthylmethyl, and the like.
As used herein, the term xe2x80x9ccycloalkylxe2x80x9d shall denote any monocyclic three to eight membered, saturated carbocyclic ring structure. Suitable examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cycloocytyl.
As used herein, unless otherwise noted, the terms xe2x80x9cheterocyclexe2x80x9d, xe2x80x9cheterocyclylxe2x80x9d and xe2x80x9cheterocycloxe2x80x9d shall denote any five or six membered monocyclic, nine or ten membered bicyclic or thirteen or fourteen membered tricyclic ring structure containing at least one heteroatom selected from the group consisting of N, O and S, optionally containing one to four additional heteroatoms, wherein the ring structure is saturated, partially unsaturated, aromatic or partially aromatic. The heterocyclyl group may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
Exemplary monocyclic heterocyclic groups can include pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropryanyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl sulfone, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dixolane and tetrahydro-1,1-dioxothienyl, dioxanyl, isothiazolidinyl, triazinyl, triazolyl and the like.
Exemplary bicyclic heterocyclic groups include benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,1-b]pyridinyl), or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), benzisoth iazolyl, benzisoxazolyl, benzodiazinyl, benzofurazanyl, benzothiopyranyl, benzotriazolyl, benzpyrazolyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, indolinyl, isochromanyl, isoindolinyl, naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl, quinazolinyl, tetrahydroquinolinyl, thienofuryl, thienopyridyl, thienothienyl and the like.
Exemplary tricyclic heterocylclic groups include phenoxazinyl, phenazinyl, phenothiazinyl, carbozolyl, perminidinyl, phenanthrolinyl, carbolinyl, naphthothienyl, thianthrenyl, and the like.
In the definition of Z, suitable examples of the 
group include pyrazol-1-yl, imidazol-1-yl, pyrrol-1-yl, 1,2,4-triazol-1-yl, 1,2,4-triazol-4-yl, 1,2,3-triazol-1-yl, aziridin-1-yl, pyrrolidin-1-yl, piperidin-1yl, piperazin-1-yl, morpholin-1-yl, 4-methyl-diazepin-1-yl, azepin-1-yl, diazepin-1-yl, 4-methyl-piperazin-1yl, and the like.
When a particular group is xe2x80x9csubstitutedxe2x80x9d (e.g., cycloalkyl, aryl, heterocyclyl, heteroaryl), that group may have one or more substituents, preferably from one to five substituents, more preferably from one to three substituents, most preferably from one to two substituents, independently selected from the list of substituents.
With reference to substituents, the term xe2x80x9cindependentlyxe2x80x9d means that when more than one of such substituents is possible, such substituents may be the same or different from each other.
Under standard nomenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. Thus, for example, a xe2x80x9cphenylalkylaminocarbonylalkylxe2x80x9d substituent refers to a group of the formula 
The term xe2x80x9csubjectxe2x80x9d as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
As used herein, the term xe2x80x9ccompositionxe2x80x9d is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
For the purposes of this invention, the term xe2x80x9cchemical libraryxe2x80x9d means a collection of molecules prepared by the method of the invention based on logical design by means of simultaneous or parallel chemical reactions. Each species of molecule in the library is referred to as a member of the library.
Abbreviations used in the specification, particularly the Schemes and Examples, are as follows:
The compounds of formula (I) wherein R2 is 
may be prepared on solid resin according to the process outlined in Scheme 1. 
More specifically, a solid resin support of formula (VII), a resin support terminated with a carbonyl chloride functional group, a known compound or compound prepared by known methods (e.g. polystyrene-carbonylchloride resin from T. M. Fyles, C. C. Leznoff, J. Weatherston, Can. J. Chem. 1978, 56, 1031 and Meyers, at al., Molecular Diversity, 1, 13 (1995); or Reaction of NovaSyn(copyright) TG carboxy Resin from Calbiochem-Novabiochem Corp with oxalyl chloride;) is reacted with a compound of formula (VIII), a known compound or compound prepared by known methods,
and then reacted with a compound of formula (IX), in a non-protic solvent such as acetonitrile, dioxane, THF, and the like, in the presence of a base such as TEA, and the like, at a temperature in the range of about 0xc2x0 C. to about reflux, to form the corresponding compound of formula (X).
Where Z is a moiety other than H, the compound of formula (X) is then reacted with a compound of formula (XI), in the presence of an acid such as TFA, and the like, in a non-protic solvent such as acetonitrile, dioxane, THF, and the like, at a temperature in the range of about 0xc2x0 C. to about reflux, resulting in cleavage of the resin support, to form the corresponding compound of formula (Ia).
When in the compound of formula (Ia) Z is H, the compound of formula (X) is reduced by transfer hydrogenation with a metal catalyst such as Pd(PPh3)4, and the like, in the presence of a source of transfer hydrogen such as triethylammonium formate, ammonium formate, and the like, wherein the source of transfer hydrogen is present in an amount equal to about 2 to 20 equivalents, preferably about 5 equivalents, in an organic solvent such as THF, dioxane, and the like, at a temperature in the range of about 40-110xc2x0 C., preferably at about reflux temperature, to form the corresponding compound of formula (Ia).
Compounds of formula (II) wherein R2 is 
may be similarly prepared on solid resin according to the process outlined in Scheme 1, with appropriate substitution of a compound of formula (XII) 
for the compound of formula (VIII), to yield the corresponding compound of formula (IIa). 
The following Examples are set forth to aid in the understanding of the invention, and are not intended and should not be construed to limit in any way the invention set forth in the claims which follow thereafter.